Low frequency glatiramer acetate therapy

ABSTRACT

A method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient.

This application claims the benefit of U.S. Provisional Application Nos.61/274,687, filed Aug. 20, 2009 and 61/337,612, filed Feb. 11, 2010. Thecontents of which are hereby incorporated by reference in theirentirety.

Throughout this application various publications are referenced by theirfull citations. The disclosures of these publications in theirentireties are hereby incorporated by reference into this application inorder to more fully describe the state of the art to which thisinvention pertains.

BACKGROUND OF THE INVENTION

Multiple Sclerosis (MS) is a chronic, debilitating disease of thecentral nervous system (CNS). MS has also been classified as anautoimmune disease. MS disease activity can be monitored by magneticresonance imaging (MRI) of the brain, accumulation of disability, aswell as rate and severity of relapses.

There are five main forms of multiple sclerosis:

1) Benign Multiple Sclerosis:

Benign multiple sclerosis is a retrospective diagnosis which ischaracterized by 1-2 exacerbations with complete recovery, no lastingdisability and no disease progression for 10-15 years after the initialonset. Benign multiple sclerosis may, however, progress into other formsof multiple sclerosis.

2) Relapsing-Remitting Multiple Sclerosis (RRMS):

Patients suffering from RRMS experience sporadic exacerbations orrelapses, as well as periods of remission. Lesions and evidence ofaxonal loss may or may not be visible on MRI for patients with RRMS.

3) Secondary Progressive Multiple Sclerosis (SPMS):

SPMS may evolve from RRMS. Patients afflicted with SPMS have relapses, adiminishing degree of recovery during remissions, less frequentremissions and more pronounced neurological deficits than RRMS patients.Enlarged ventricles, which are markers for atrophy of the corpuscallosum, midline center and spinal cord, are visible on MRI of patientswith SPMS.

4) Primary Progressive Multiple Sclerosis (PPMS);

PPMS is characterized by a steady progression of increasing neurologicaldeficits without distinct attacks or remissions. Cerebral lesions,diffuse spinal cord damage and evidence of axonal loss are evident onthe MRI of patients with PPMS.

5) Progressive-Relapsing Multiple Sclerosis (PRMS):

PRMS has periods of acute exacerbations while proceeding along a courseof increasing neurological deficits without remissions. Lesions areevident on MRI of patients suffering from PRMS (Multiple sclerosis: itsdiagnosis, symptoms, types and stages, 2003, albany.net/.about.tjc/multiple-sclerosis.html; What are the Types of Multiple Sclerosis?,2005, <imaginis.com/multiple-sclerosis/types-of-ms.asp? mode=1>).

Chronic progressive multiple sclerosis is a term used to collectivelyrefer to SPMS, PPMS, and PRMS (Types of Multiple Sclerosis (MS), 2005,<themcfox.com/multiple-sclerosis/types-of-ms/types-of-multi-ple-sclerosis.htm>).The relapsing forms of multiple sclerosis are SPMS with superimposedrelapses, RRMS and PRMS.

Glatiramer acetate (GA), a mixture of polypeptides which do not all havethe same amino acid sequence, is marketed under the tradename Copaxone®.GA comprises the acetate salts of polypeptides containing L-glutamicacid, L-alanine, L-tyrosine and L-lysine at average molar fractions of0.141, 0.427, 0.095 and 0.338, respectively. The average molecularweight of Copaxone® is between 5,000 and 9,000 daltons. (“Copaxone”,Physician's Desk Reference, (2005), Medical Economics Co., Inc.,(Montvale, N.J.), 3115.) Chemically, glatiramer acetate is designatedL-glutamic acid polymer with L-alanine, L-lysine, L-tyrosine, acetate(salt).

Its structural formula is:

(Glu,Ala,Lys,Tyr)x.X CH₃COOH

(C₅H₉NO₄.C₃H₇NO₂.C₆H₁₄N₂O₂.C₉H₁₁NO₃)x.x CHO

CAS-147245-92-9

Copaxone® (“Copaxone”, Full Prescribing Information, (February, 2009),FDA Marketing Label) (20 mg glatiramer acetate daily injection) is anapproved therapy for patients with relapsing remitting multiplesclerosis (RRMS), including patients who have experienced a firstclinical episode and have MRI features consistent with multiplesclerosis.

GA has also been disclosed for use in the treatment of other autoimmunediseases (U.S. Patent Publication No. 2002/0055466 A1 (R. Aharoni etal.), inflammatory non-autoimmune diseases (U.S. Patent Publication No.2005/0014694 A1 (V. Wee Yong et al.); and U.S. Patent Application No.2002/0077278 A1, published Jun. 20, 2002 (Young et al.)) and otherdiseases (U.S. Patent Publication Nos. 2003/0004099 A1 and 2002/0037848A1 (Eisenbach-Schwartz, et al.); U.S. Pat. No. 6,514,938 B1, issued Feb.4, 2003 (Gad et al.); PCT International Publication No. WO 01/60392,published Aug. 23, 2001 (Gilbert et al.); PCT International PublicationNo. WO 00/27417, published May 19, 2000 (Aharoni et al.); and PCTInternational Publication No. WO 01/97846, published Dec. 27, 2001(Moses et al.).

The 20 mg/day subcutaneous (s.c.) dose has been shown to reduce thetotal number of enhancing lesions in MS patients as measured by MRI (G.Comi et al., European/Canadian Multicenter, Double-Blind, Randomized,Placebo-Controlled Study of the Effects of Glatiramer Acetere onMagnetic Resonance Imaging-Measured Disease Activity and Burden inPatients with Relapsing Multiple Sclerosis, Ann. Neurol. 49:290-297(2001)).

Safety data accumulated for GA in clinical trials shows that the drugproduct is safe and well tolerated.

Disclosed is an effective low frequency dosage regimen of GAadministration to patients suffering from a relapsing form of multiplesclerosis, including patients who have experienced a first clinicalepisode and have MRI features consistent with multiple sclerosis.

SUMMARY OF THE INVENTION

This invention provides a method of alleviating a symptom ofrelapsing-remitting multiple sclerosis in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined to be at high risk ofdeveloping clinically definite multiple sclerosis comprisingadministering to the human patient three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection soas to thereby alleviate the symptom of the patient.

This invention also provides a method of increasing the tolerability ofGA treatment in a human patient suffering from relapsing-remittingmultiple sclerosis or a patient who has experienced a first clinicalepisode and is determined to be at high risk of developing clinicallydefinite multiple sclerosis which comprises reducing the frequency ofsubcutaneous injections of a pharmaceutical composition comprising atherapeutically effective dose of glatiramer acetate to three times overa period of seven days with at least one day between every injection.

In another embodiment, the therapeutically effective dose of glatirameracetate is 40 mg/ml.

This invention also provides a use of glatiramer acetate in thepreparation of a medicament for treating relapsing-remitting multiplesclerosis in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the administration pattern of the medicamentis three subcutaneous injections of a therapeutically effective dose ofglatiramer acetate over a period of seven days with at least one daybetween every subcutaneous injection.

This invention additionally provides a use of glatiramer acetate in thepreparation of a medicament for treating relapsing-remitting multiplesclerosis in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the medicament is prepared for anadministration pattern of three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection.

This invention yet also provides a use of glatiramer acetate in hepreparation of a medicament for increasing the tolerability of GAtreatment in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the administration pattern of the medicamentis three subcutaneous injections of a therapeutically effective dose ofglatiramer acetate over a period of seven days with at least one daybetween every subcutaneous injection.

This invention further provides a use of glatiramer acetate in thepreparation of a medicament for increasing the tolerability of GAtreatment in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the medicament is prepared for anadministration pattern of three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection.

This invention provides glatiramer acetate for use in treatingrelapsing-remitting multiple sclerosis in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined to be at high risk ofdeveloping clinically definite multiple sclerosis by three subcutaneousinjections over a period of seven days with at least one day betweenevery subcutaneous injection.

This invention also provides glatiramer acetate for use in increasingthe tolerability of GA treatment in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined to be at high risk ofdeveloping clinically definite multiple sclerosis by three subcutaneousinjections over a period of seven days with at least one day betweenevery subcutaneous injection.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides a method of alleviating a symptom ofrelapsing-remitting multiple sclerosis in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined to be at high risk ofdeveloping clinically definite multiple sclerosis comprisingadministering to the human patient three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection soas to thereby alleviate the symptom of the patient.

In another embodiment, there are three injections for every seven daysand there must be at least one day between each injection. In a furtherembodiment, possible injection schedules include Day 1, Day 3, Day 5;Day 1, Day 3, Day 6; Day 1, Day 3, Day 7; Day 1, Day 4, Day 6; Day 1,Day 4, Day 7; Day 1, Day 5, Day 7; Day 2, Day 4, Day 6; Day 2, Day 4,Day 7; Day 2, Day 5, Day 7; or Day 3, Day 5, Day 7.

In an embodiment, alleviating a symptom comprises reducing the frequencyof relapses.

In yet another embodiment, alleviating a symptom comprises reducing themean cumulative number of Gd-enhancing lesions in the brain of thepatient.

In another embodiment, alleviating a symptom comprises reducing the meannumber of new T₂ lesions in the brain of the patient.

In a further embodiment, alleviating a symptom comprises reducing thecumulative number of enhancing lesions on T₁-weighted images in thepatient.

In another embodiment, alleviating a symptom comprises reducing brainatrophy in the patient.

In another embodiment, alleviating a symptom comprises increasing thetime to a confirmed relapse in the patient.

In another embodiment, alleviating a symptom comprises reducing thetotal number of confirmed relapses in the patient.

In another embodiment, alleviating a symptom comprises reducing theprogression of MRI-monitored disease activity in the patient.

In another embodiment, alleviating a symptom comprises reducing totalvolume of T₂ lesionsin the patient.

In another embodiment, alleviating a symptom comprises reducing thenumber of new hypointense lesions on enhanced T₁ scans in the patient.

In another embodiment, alleviating a symptom comprises reducing thetotal volume of hypointense lesions on enhanced T₁ scans in the patient.

In another embodiment, alleviating a symptom comprises reducing thelevel of disability as measured by EDS'S Score in the patient.

In another embodiment, alleviating a symptom comprises reducing thechange in EDSS Score in the patient.

In another embodiment, alleviating a symptom comprises reducing thechange in Ambulation Index in the patient.

In another embodiment, alleviating a symptom comprises reducing thelevel of disability as measured by EuroQoL (EQ5D) questionnaire in thepatient.

In another embodiment, alleviating a symptom comprises reducing thelevel of disability as measured by the work productivity and activitiesimpairment—General Health (WPAI-GH) questionnaire in the patient.

In an additional embodiment, the pharmaceutical composition is in aprefilled syringe for self administration by the patient.

In yet another embodiment, the therapeutically effective dose ofglatiramer acetate is 40 mg/ml. In a further embodiment, thetherapeutically effective dose of glatiramer acetate is 40 mg/0.75 ml.

In a further embodiment, the patient has not received glatiramer acetatetherapy prior to initiation of the subcutaneous injections.

In an embodiment, the pharmaceutical composition is in the form of asterile solution.

In another embodiment, the pharmaceutical composition further comprisesmannitol.

In yet another embodiment, the pharmaceutical composition has a pH inthe range of 5.5 to 8.5.

In an embodiment, the pharmaceutical composition has a pH in the rangeof 5.5 to 7.0.

In an embodiment the frequency of an immediate post injection reactionor the frequency of an injection site reaction is reduced relative todaily subcutaneous administration of 20 mg glatiramer acetate.

This invention also provides a method of increasing the tolerability ofGA treatment in a human patient suffering from relapsing-remittingmultiple sclerosis or a patient who has experienced a first clinicalepisode and is determined to be at high risk of developing clinicallydefinite multiple sclerosis which comprises reducing the frequency ofsubcutaneous injections of a pharmaceutical composition comprising atherapeutically effective dose of glatiramer acetate to three times overa period of seven days with at least one day between every injection.

In another embodiment, increasing the tolerability of GA treatment inthe human patient suffering from a relapsing form of multiple sclerosiscomprises reducing the frequency of an immediate post injectionreaction.

In yet another embodiment, the immediate post injection reaction ispalpitations, feeling hot, flushing, hot flushes, tachycardia, dyspnoea,chest discomfort, chest pain, non-cardiac chest, asthenia, back pain,bacterial infection, chills, cyst, face edema, fever, flu syndrome,infection, injection site erythema, injection site hemorrhage,injection. site induration, injection site inflammation, injection sitemass, injection site pain, injection site pruritus, injection siteurticaria, injection site welt, neck pain, pain, migrane, syncope,tachycardia, vasodilatation, anorexia, diarrhea, gastroenteritis,gastrointestinal disorder, nausea, vomiting, ecchymosis, peripheraledema, arthralgia, agitation, anxiety, confusion, foot drop, hypertonia,nervousness, nystagmus, speech disorder, tremor, vertigo, bronchitis,dyspnea, laryngismus, rhinitis, erythema, herpes simplex, pruritus,rash, skin nodule, sweating, urticaria, ear pain, eye disorder,dysmenorrheal, urinary urgency, or vaginal moniliasis.

In an additional embodiment, increasing the tolerability of GA treatmentin the human patient suffering from a relapsing form of multiplesclerosis comprises reducing the frequency of an injection sitereaction.

In a further embodiment, the injection site reaction is erythema,hemorrhage, induration, inflammation, mass, pain, pruritus, urticaria,or welt that occurs immediately around the site of injection.

In an embodiment, a single clinical attack includes a clinical episodeof optic neuritis, blurring of vision, diplopia, involuntary rapid eyemovement, blindness, loss of balance, tremors, ataxia, vertigo,clumsiness of a limb, lack of coordination, weakness of one or moreextremity, altered muscle tone, muscle stiffness, spasms, tingling,paraesthesia, burning sensations, muscle pains, facial pain, trigeminalneuralgia, stabbing sharp pains, burning tingling pain, slowing ofspeech, slurring of words, changes in rhythm of speech, dysphagia,fatigue, bladder problems (including urgency, frequency, incompleteemptying and incontinence), bowel problems (including constipation andloss of bowel control), impotence, diminished sexual arousal, loss ofsensation, sensitivity to heat, loss of short term memory, loss ofconcentration, or loss of judgment or reasoning.

In another embodiment, prior to administration the patient has at least1 cerebral lesion detectable by an MRI scan and suggestive of multiplesclerosis.

In yet another embodiment, the lesion is associated with brain tissueinflammation, myelin sheath damage or axonal damage.

In an additional embodiment, the lesion is a demyelinating white matterlesion visible on brain MRI.

In a further embodiment, the white matter lesions are at least 3 mm indiameter.

This invention also provides a use of glatiramer acetate in thepreparation of a medicament for treating relapsing-remitting multiplesclerosis in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the administration pattern of the medicamentis three subcutaneous injections of a therapeutically effective dose ofglatiramer acetate over a period of seven days with at least one daybetween every subcutaneous injection.

This invention additionally provides a use of glatiramer acetate in thepreparation of a medicament for treating relapsing-remitting multiplesclerosis in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the medicament is prepared for anadministration pattern of three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection.

This invention yet also provides a use of glatiramer acetate in thepreparation of a medicament for increasing the tolerability of GAtreatment in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the administration pattern of the medicamentis three subcutaneous injections of a therapeutically effective dose ofglatiramer acetate over a period of seven days with at least one daybetween every subcutaneous injection.

This invention further provides a use of glatiramer acetate in thepreparation of a medicament for increasing the tolerability of GAtreatment in a human patient suffering from relapsing-remitting multiplesclerosis or a patient who has experienced a first clinical episode andis determined to be at high risk of developing clinically definitemultiple sclerosis wherein the medicament is prepared for anadministration pattern of three subcutaneous injections of atherapeutically effective dose of glatiramer acetate over a period ofseven days with at least one day between every subcutaneous injection.

This invention provides glatiramer acetate for use in treatingrelapsing-remitting multiple sclerosis in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined tm be at high risk ofdeveloping clinically definite multiple sclerosis by three subcutaneousinjections over a period of seven days with at least one day betweenevery subcutaneous injection.

This invention also provides glatiramer acetate for use in increasingthe tolerability of GA treatment in a human patient suffering fromrelapsing-remitting multiple sclerosis or a patient who has experienceda first clinical episode and is determined to be at high risk ofdeveloping clinically definite multiple sclerosis by three subcutaneousinjections over a period of seven days with at least one day betweenevery subcutaneous injection.

Definitions

As used herein, immediate post injection reaction (IRPR) refers to areaction such as, palpitations, feeling hot, flushing, hot flushes,tachycardia, dyspnoea, chest discomfort, chest pain, and non-cardiacchest pain that occurs immediately following injection. Reactions mayalso include asthenia, back pain, bacterial infection, chills, cyst,face edema, fever, flu syndrome, infection, injection site erythema,injection site hemorrhage, injection site induration, injection siteinflammation, injection site mass, injection site pain, injection sitepruritus, injection site urticaria, injection site welt, neck pain,pain, migrane, syncope, tachycardia, vasodilatation, anorexia, diarrhea,gastroenteritis, gastrointestinal disorder, nausea, vomiting,ecchymosis, peripheral edema, arthralgia, agitation, anxiety, confusion,foot drop, hypertonia, nervousness, nystagmus, speech disorder, tremor,vertigo, bronchitis, dyspnea, laryngismus, rhinitis, erythema, herpessimplex, pruritus, rash, skin nodule, sweating, urticaria, ear pain, eyedisorder, dysmenorrheal, urinary urgency, and vaginal moniliasis.

As used herein, injection site reaction (ISR) refers to a reaction suchas erythema, hemorrhage, induration, inflammation, mass, pain, pruritus,urticaria, and welt that occurs immediately around the site ofinjection.

As used herein, “tolerability” relates to the level of discomfortassociated with GA treatment. Tolerability is associated with thefrequency and severity of post injection reactions and injection sitereactions. Tolerability influences the period that a patient can followGA treatment.

As used herein, the term Gd-enhancing lesions, refers to lesions thatresult from a breakdown of the blood-brain barrier, which appear incontrast studies using gandolinium contrast agents. Gandoliniumenhancement provides information as to the age a lesion, as Gd-enhancinglesions typically occur within a six week period of lesion formation.

As used herein, the term T₁-weighted MRI images refers to an MR-imagethat emphasizes T₁ contrast by which lesions may be visualized. Abnormalareas in a T₁-weighted MRI image are “hypointense” and appear as darkspots. These spots are generally older lesions.

As used herein, the term T₂-weighted MRI image, refers to an MR-imagethat emphasizes T₂ contrast by which lesions may be visualized. T₂lesions represent new inflammatory activity.

As used herein, the term “unit dosage” refers to physically discreteunits suited as single administration dose for a subject to be treated,containing a therapeutically effective quantity of active compound inassociation with the required pharmaceutical carrier, e.g., a syringe.

As used herein, clinically isolated syndrome (CIS) refers to 1) a singleclinical attack suggestive of MS and 2) at least one lesion suggestiveof MS. As an example, the patient has at least 1 cerebral lesiondetectable by an MRI scan and suggestive of multiple sclerosis. As anadditional example the lesion is associated with brain tissueinflammation, myelin sheath damage or axonal damage. As another examplethe lesion is a demyelinating white matter lesion visible on brain MRI.In a further example, the white matter lesions are at least 3 mm indiameter.

The term “single clinical attack” is used synonymously with “firstclinical episode”, “first clinical attack”, and “first clinical event”which, for example, presents as a clinical episode of optic neuritis,blurring of vision, diplopia, involuntary rapid eye movement, blindness,loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack ofcoordination, weakness of one or more extremity, altered muscle tone,muscle stiffness, spasms, tingling, paraesthesia, burning sensations,muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains,burning tingling pain, slowing of speech, slurring of words, changes inrhythm of speech, dysphagia, fatigue, bladder problems (includingurgency, frequency, incomplete emptying and incontinence), bowelproblems (including constipation and loss of bowel control), impotence,diminished sexual arousal, loss of sensation, sensitivity to heat, lossof short term memory, loss of concentration, or loss of judgment orreasoning.

As used herein, the criteria, as defined by Poser et al. Neurology,March 1983, 13 (3): 227-230, used to determine if a subject meets thecondition consistent with clinically definite multiple sclerosis (CDMS)are:

-   -   Two attacks and clinical evidence of two separate lesions or    -   Two attacks; clinical evidence of one lesion and paraclinical        evidence of another separate lesion.

An attack (also referred to as an exacerbation, flare, or relapse,) isdefined clinically as the sudden appearance or worsening of a symptom orsymptoms of neurological dysfunction, with or without objectiveconfirmation.

Clinical evidence of a lesion is defined as signs of neurologicaldysfunction demonstrable by neurological examination. An abnormal signconstitutes clinical evidence even if no longer present, but wasrecorded in the past by a competent examiner.

Paraclinical evidence of a lesion is defined as the demonstration bymeans of various tests and procedures of the existence of a lesion ofthe CNS that has not produced clinical signs but that may or may nothave caused symptoms in the past. Such evidence may be derived from thehot-bath test, evoked response studies, neuroimaging, and expertneurological assessment. These tests are considered to be extensions ofthe neurological examination and not laboratory procedures.

As used herein, the term “glatiramoid” refers a complex mixture of theacetate salts of synthetic polypeptides, non-uniform with respect tomolecular weight and sequence.

This invention is illustrated in the Examples section which follows.This section is set forth to aid in an understanding of the inventionbut is not intended to, and should not be construed to, limit in any waythe invention as net forth in the claims which follow thereafter.

EXPERIMENTAL DETAILS Example 1

A multinational, multicenter, randomized, phase III parallel-group studyperformed in subjects with Relapsing-Remitting Multiple Sclerosis (RRMS)to assess the efficacy, safety and tolerability of Glatiramer Acetate(GA) injection 40 mg/ml administered three times weekly by subcutaneousinjection over placebo in a double-blind design.

Methods:

The study is designed to select three days a week for injection. Threeinjections are administered for every seven days and there must be atleast one day between each injection.

Study Duration:

Screening phase: 1 month

Placebo Controlled (PC) Phase: 12 months of 40 mg/ml or matching placeboadministered three times weekly by subcutaneous injection.

Open Label (OL) Extension: All subjects will continue treatment with theGA 40 mg/ml administered three times a week, until this dose iscommercially available for the treatment of relapsing remitting multiplesclerosis (RRMS) patients or until the development of this dose for MSis stopped by the Sponsor.

Study Population:

Subjects with RRMS

Number of Subjects:

1350 subjects

Study Objective(s):

To assess the efficacy, safety and tolerability of Glatiramer Acetate(GA) injection 40 mg/ml administered three times weekly compared toplacebo in a double-blind study design.

Study Design:

Eligible subjects are randomized in a 2:1 ratio (40 mg:placebo) andassigned to one of the following three treatment arms:

-   -   1. 40 mg s.c. GA three times weekly (900 subjects)    -   2. Matching placebo three times weekly (450 subjects)

During the PC phase, subjects are evaluated at study sites for a totalof 7 scheduled visits at months: −1 (screening), 0 (baseline), 1, 3, 6,9, and 12 (End of PC phase).

Subjects successfully completing the study are offered the opportunityto enter into an open label extension in which all subjects willcontinue treatment with 40 mg/ml GA dose. This is done until the 40mg/ml GA dose is commercially available for the treatment of relapsingremitting multiple sclerosis (RRMS) patients or until the development ofthis dose regimen is stopped by the Sponsor.

The termination visit of the PC phase will serve as the baseline visitof the OL phase. This phase will include scheduled visits every 3 monthsfor the first 12 months, then scheduled visits every 6 months and willbe completed with a termination visit.

During the study, the following assessments are performed (regardless ofthe treatment assignment) at the specified time points:

-   -   Vital signs are measured at each study visit.    -   A physical examination is performed at months −1 (screening), 0        (baseline) 6, 12 (end of PC phase) and every months thereafter.        In addition, a physical examination will be performed at the        termination visit of the OL phase.    -   The following safety clinical laboratory tests are performed:        -   Complete blood count (CBC) with differential—at all            scheduled visits in the PC phase, and every 12 months            thereafter. In addition this test will be performed at the            termination visit of the OL phase.        -   Serum chemistry (including electrolytes, creatinine, urea            and liver enzymes) and urinalysis—at all scheduled visits in            the PC phase, and every 12 months thereafter. In addition            this test will be performed at the termination visit of the            OL phase.        -   Serum β-hCG in women of child-bearing potential is performed            at months −1 (screening), 0 (baseline), 12 (end of PC            phase), and every 12 months thereafter. In addition this            test will be performed at the termination visit of the OL            phase.    -   ECG is performed at months −1 (screening), 0 (baseline), 12 (end        of PC phase), and every 12 months thereafter. In addition an ECG        will be performed at the termination visit of the OL phase.    -   Chest X-ray is performed at month −1 (screening) if not        performed within 6 months prior to screening visit.    -   Adverse Events (AEs) are monitored throughout the study.    -   Concomitant Medications are monitored throughout the study.    -   Neurological evaluations, including Neurostatus [Functional        Systems (FS), Expanded Disability Status Scale (EDSS),        Ambulation Index (AI)] are performed at months −1 (screening), 0        (baseline), 3, 6, 9, 12 (end of PC phase) and every 6 months        thereafter. In addition, a neurological examination are        performed at the termination visit of the OL phase.    -   The general health status is assessed by the EuroQoL (EQ5D)        questionnaire at months 0 (baseline) and 12 (end of PC phase).    -   Additional quality of life parameters are assessed by the WPAI        (Work Productivity and Activities Impairment) Questionnaire at        month 0 (baseline), 3, 6, 9 and 12 (end of PC phase).    -   All subjects undergo MRI scans at months 0 (13-7 days prior to        baseline visit), 6 and 12 (end of PC phase). Following the        results of the PC phase, the Sponsor may decide to perform an        MRI scan at the termination visit of the OL phase.    -   Relapses are confirmed/monitored throughout the study.

Ancillary Studies:

-   -   Blood samples for determination of anti-GA antibodies are        collected for all subjects at months 0 (baseline), 1, 3, 6, 9,        12 (end of PC phase), 18 and 24.    -   Blood samples for evaluation of PBL proliferation in response to        GA, as well as other immunological parameters, are collected in        a subset of subjects at months 0 (baseline), 1, 3, 6, and 12        (end of PC phase).    -   Blood samples for Pharmacogenetic (PGx) analysis are collected        for all subjects twice during the study, preferably at month 0        (baseline) and month 1.

The allowed treatment for a multiple sclerosis relapse will beintravenous methylprednisolone 1 gr/day for up to 5 consecutive days.

Re-Consent Criteria

In case of a confirmed diagnosis of MS relapse (as defined in theprotocol), or in case of an increase in EDSS of 1.5 points or more,sustained for at least 3 months, during the placebo-controlled phase,the following actions are taken:

-   -   The subject is reminded of the current available MS        medications/treatments and the opportunity to terminate the        study.    -   The subject is requested to re-sign an informed consent form if        he/she chooses to continue to participate in the study, in the        same treatment assignment.

The study is closely monitored through the study course by the sponsor'spersonnel as well as by an external independent data monitoringcommittee (DMC) in order to ensure subjects' welfare.

Inclusion/Exclusion: Inclusion Criteria:

-   -   Subjects must have a confirmed and documented MS diagnosis as        defined by the Revised McDonald criteria (Ann Neurol 2005:        58:840-846), with a relapsing-remitting disease course.    -   Subjects must be ambulatory with an EDSS score of 0-5.5 in both        screening and baseline visits.    -   Subjects must be in a relapse-free, stable neurological        condition and free of corticosteroid treatment [intravenous        (IV), intramuscular (IM) and/or per no (PO)] or ACTH 30 days        prior to screening (month −1) and between screening (month -1)        and baseline (month 0) visits.    -   Subjects must have had experienced one of the following:        -   At least one documented relapse in the 12 months prior to            screening, or        -   At least two documented relapses in the 24 months prior to            screening, or        -   One documented relapse between 12 and 24 months prior to            screening with at least one documented T₁-Gd enhancing            lesion in an MRI performed within 12 months prior to            screening.    -   Subjects must be between 18 and 55 years of age, inclusive.    -   Women of child-bearing potential must practice an acceptable        method of birth control [acceptable methods of birth control in        this study include: surgical sterilization, intrauterine        devices, oral contraceptive, contraceptive patch, long-acting        injectable contraceptive, partner's vasectomy or a        double-barrier method (condom or diaphragm with spermicide)].    -   Subjects must be able to sign and date a written informed        consent prior to entering the study.    -   Subjects must be willing and able to comply with the protocol        requirements for the duration of the study.

Exclusion Criteria:

-   -   Subjects with progressive forms of MS.    -   Use of experimental or investigational drugs, and/or        participation in drug clinical studies within the 6 months prior        to screening.    -   Use of immunosuppressive (including Mitoxantrone (Novantrone) or        cytotoxic agents within 6 months prior to the screening visit.    -   Previous use of either natalizumab (Tysabri®) or any other        monoclonal antibodies within 2 years prior to screening.    -   Use of cladribine within 2 years prior to screening.    -   Previous treatment with immunomodulators (including IFNβ 1a and        1b, and IV Immunoglobulin (IVIg) within 2 months prior to        screening.    -   Previous use of GA or any other glatiramoid.    -   Chronic (more than 30 consecutive days) systemic (IV, PO or IM)        corticosteroid treatment within 6 months prior to screening        visit.

Previous total body irradiation or total lymphoid irradiation.

-   -   Previous stem-cell treatment, autologous bone marrow        transplantation or allogenic bone marrow transplantation.    -   Known human immunodeficiency virus (HIV) positive status.        Pregnancy or breastfeeding.    -   Subjects with a clinically significant or unstable medical or        surgical condition that would preclude safe and complete study        participation, as determined by medical history, physical exams,        ECG, abnormal laboratory tests and chest X-ray. Such conditions        may include hepatic, renal or metabolic diseases, systemic        disease, acute infection, current malignancy or recent history        (5 years) of malignancy, major psychiatric disorder, history of        drug and/or alcohol abuse and allergies that could be        detrimental according to the investigator's judgment.    -   A known history of sensitivity to Gadolinium.    -   Inability to successfully undergo MRI scanning.    -   A known drug hypersensitivity to mannitol.

Route and Dosage Form:

-   -   Glatiramer Acetate 40 mg in 1 ml for subcutaneous injection in a        pre-filled syringe (PFS), administered three times a week.    -   Matching placebo injection (mannitol in 1 ml WFI) for        subcutaneous injection in a pre-filled syringe (PFS).

Outcome Measures: Primary Outcome Measure:

-   -   The total number of confirmed relapses during the 12 month PC        phase.

Secondary Outcome Measure:

-   -   The number of new T₂ lesions at month 12 (end of PC phase) as        compared to baseline scan.    -   The cumulative number of enhancing lesions on T₁-weighted images        taken at months 6 and 12 (end of PC phase).    -   Brain atrophy as defined by the percent brain volume change from        baseline to month 12 (end of PC phase).

Exploratory Endpoints:

The following assessments are presented in an exploratory manner.

-   -   The time to the first confirmed relapse during the        placebo-controlled phase.    -   The proportion of relapse-free subjects during the        placebo-controlled phase.    -   The total number of confirmed relapses during the        placebo-controlled phase requiring hospitalization and/or IV        steroids.    -   The proportion (%) of subjects with confirmed EDSS progression        during the placebo-controlled phase (progression of at least 1        EDSS point sustained for at least 3 months).    -   Change from baseline to month 12 (end of placebo-controlled        phase) in EDSS Score.    -   Change from baseline to month 12 (end of placebo-controlled        phase) in Ambulation Index.    -   The total volume of T₂ lesions at month 12 (end of        placebo-controlled phase)    -   The number of new hypointense lesions on enhanced T₁ scans at        month 12 (end of placebo-controlled phase) as compared to the        baseline scan.    -   The total volume of hypointense lesions on enhanced T₁ scans at        month 12 (end of placebo-controlled phase).    -   Brain atrophy as defined by the percentage change from baseline        to month 12 (end of placebo-controlled phase) in normalized gray        matter volume and in normalized white matter volume.    -   The general health status, as assessed by the EuroQoL (EQ5D)        questionnaire.    -   Assessment of the effect of general health and symptom severity        on work, using the work productivity and activities impairment        General Health (WPAI-GH) questionnaire.

Safety and Tolerability Outcome Measures: Safety:

-   -   Adverse events    -   Vital signs    -   ECG findings    -   Clinical laboratory parameters

Tolerability:

-   -   Proportion of subjects (%) who prematurely discontinued from the        study, reason of discontinuation and the time to withdrawal.    -   Proportion of subjects (%) who prematurely discontinued from the        study due to AEs and the time to withdrawal.

Statistical Considerations:

The sample size considerations for the study are based on the followingassumptions:

-   -   An individual subject's number of confirmed relapses during a        one year period reflects a Poisson process with an individual        rate of λi, and this individual subject rates λi are        exponentially distributed with mean 1/θ, where θ is the        population's annualized relapse rate. This approach models the        total number of confirmed relapses as an Over Dispersed Poisson        distribution.    -   The expected annualized relapse rate in an untreated subject        population is θ=0.35 relapses per year.    -   Treatment with 40 mg s.c. GA three times weekly reduces the        subject population annualized relapse rate by 30% or more when        compared to the placebo group. That is, the expected annualized        relapse rate of the GA treated populations is θ=0.245 relapses        per year or less.

In addition, the following are also incorporated in the sample sizecalculation:

-   -   15% of the subjects drop out during the treatment duration. This        drop out rate is taken into account in the calculations, as on        the average, a subject who drops out of the study contributes 6        months of exposure to the treatment

Hochberg's step-up modification to Bonferroni's method is used tomaintain the experiment-wise type-I error when comparing multipletreatment arms to placebo, and the p-values for the IAs are calculatedusing the O'brien-Fleming alpha spending functions.

A simulation study accounting for the above underlying assumptions usedthe Quasi-Likelihood (over-dispersed) Poisson Regression (SAS® PROCGENMOD), revealed that a total of 1350 subjects (900 subjects in the 40mg GA arm, and 450 subjects to the placebo arm) provide approximately90% power to detect a significant difference in the total number ofconfirmed relapses as described above.

The analysis of the total numbers of confirmed relapses during the studyperiod is based on baseline adjusted Quasi-Likelihood (over-dispersed)Poisson Regression.

The analysis of the number of new T₂ lesions at month 12 and of thecumulative number of enhancing lesions on T₁-weighted images taken atmonths 6 and 12 is based on baseline-adjusted Negative BinomialRegression.

The analysis of Brain Atrophy will be based on Analysis of Covariance(ANCOVA).

Results Primary Outcome Measure:

Treatment with 40 mg s.c. GA three times weekly reduces the subjectpopulation annualized relapse rate by 30% or more when compared to theplacebo group. Treatment with 40 mg s.c. GA three times weekly is atleast as effective as 20 mg s.c. GA daily administration at reducing thesubject population annualized relapse rate.

Secondary Outcome Measures:

-   -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the number of new T₂ lesions at month 12. Treatment with        40 mg s.c. GA three times weekly is at least as effective as 20        mg s.c. GA daily administration at reducing the number of new T₂        lesions at month 12.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the cumulative number of enhancing lesions on        T₁-weighted images taken at months 6 and 12. Treatment with 40        mg s.c. GA three times weekly is at least as effective as 20 mg        s.c. GA daily administration at reducing the cumulative number        of enhancing lesions on T₁-weighted images taken at months 6 and        12.

Treatment with 40 mg s.c. GA three times weekly significantly reducesbrain atrophy as defined by the percent brain volume change frombaseline to month 12. Treatment with 40 mg s.c. GA three times weekly isat least as effective as 20 mg s.c. GA daily administration at reducingbrain atrophy as defined by the percent brain volume change frombaseline to month 12.

Exploratory Endpoints:

-   -   Treatment with 40 mg s.c. GA three times weekly significantly        increases the time to the first confirmed relapse during the        placebo-controlled phase. Treatment with 40 mg s.c. GA three        times weekly is at least as effective as 20 mg s.c. GA daily        administration at increasing the time to the first confirmed        relapse during the placebo-controlled phase.    -   Treatment with 40 mg s.c. GA three times weekly significantly        increases the proportion of relapse-free subjects during the        placebo-controlled phase. Treatment with 40 mg s.c. GA three        times weekly is at least as effective as 20 mg s.c. GA daily        administration at increasing the proportion of relapse-free        subjects during the placebo-controlled phase.    -   Treatment with 40 mg s.c. GA three times weekly significantly        increases the proportion of relapse-free subjects during the        placebo-controlled phase. Treatment with 40 mg s.c. GA three        times weekly is at least as effective as 20 mg s.c. GA daily        administration at increasing the proportion of relapse-free        subjects during the placebo-controlled phase.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the total number of confirmed relapses during the        placebo-controlled phase requiring hospitalization and/or IV        steroids. Treatment with 40 mg s.c. GA three times weekly is at        least as effective as 20 mg s.c. GA daily administration at        reducing the total number of confirmed relapses during the        placebo-controlled phase requiring hospitalization and/or IV        steroids.

Treatment with 40 mg s.c. GA three times weekly significantly reducesthe progression of MRI-monitored disease activity in the patient.Treatment with 40 mg s.c. GA three times weekly is at least as effectiveas 20 mg s.c. GA daily administration at reducing the progression ofMRI-monitored disease activity in the patient.

Treatment with 40 mg s.c. GA three times weekly significantly reducesthe total volume of T₂ lesions at month 12. Treatment with 40 mg s.c. GAthree times weekly is at least as effective as 20 mg s.c. GA dailyadministration at reducing total volume of T₂ lesions at month 12.

-   -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the number of new hypointense lesions on enhanced T₁        scans at month 12 as compared to the baseline scan. Treatment        with 40 mg s.c. GA three times weekly is at least as effective        as 20 mg s.c. GA daily administration at reducing the number of        new hypointense lesions on enhanced T₁ scans at month 12 as        compared to the baseline scan.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the total volume of hypointense lesions on enhanced T₁        scans at month 12. Treatment with 40 mg s.c. GA three times        weekly is at least as effective as 20 mg s.c. GA daily        administration at reducing the total volume of hypointense        lesions on enhanced T₁ scans at month 12.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces brain atrophy as defined by the percentage change from        baseline to month 12 in normalized gray matter volume and in        normalized white matter volume. Treatment with 40 mg s.c. GA        three times weekly is at least as effective as 20 mg s.c. GA        daily administration at reducing brain atrophy as defined by the        percentage change from baseline to month 12 in normalized gray        matter volume and in normalized white matter volume.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the level of disability as measured by EDSS Score.        Treatment with 40 mg s.c. GA three times weekly is at least as        effective as 20 mg s.c. GA daily administration at reducing the        level of disability as measured by EDSS Score.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the proportion (%) of subjects with confirmed EDSS        progression during the placebo-controlled phase (progression of        at least 1 EDSS point sustained for at least 3 months).        Treatment with 40 mg s.c. GA three times weekly is at least as        effective as 20 mg s.c. GA daily administration at reducing        proportion (%) of subjects with confirmed EDSS progression        during the placebo-controlled phase (progression of at least 1        EDSS point sustained for at least 3 months).    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the change from baseline to month (end of        placebo-controlled phase) in EDSS Score. Treatment with 40 mg        s.c. GA three times weekly is at least as effective as 20 mg        s.c. GA daily administration at reducing the change from        baseline to month 12 (end of placebo-controlled phase) in EDSS        Score.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the change from baseline to month 12 (end of        placebo-controlled phase) in Ambulation Index. Treatment with 40        mg s.c. GA three times weekly is at least as effective as 20 mg        s.c. GA daily administration at reducing the change from        baseline to month 12 (end of placebo-controlled phase) in        Ambulation Index.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the level of disability as measured by EuroQoL (EQ5D)        questionnaire. Treatment with 40 mg s.c. GA three times weekly        is at least as effective as 20 mg s.c. GA daily administration        at reducing the level of disability as measured by EuroQoL        (EQ5D) questionnaire.    -   Treatment with 40 mg s.c. GA three times weekly significantly        reduces the level of disability as measured by the work        productivity and activities impairment—General Health (WPAI-GH)        questionnaire. Treatment with 40 mg s.c. GA three times weekly        is at least as effective as 20 mg s.c. GA daily administration        at reducing the level of disability as measured by the work        productivity and activities impairment General Health (WPAI-GH)        questionnaire.

Discussion

A significant drawback to GA therapy is the requirement of dailyinjections, which can be inconvenient. Moreover, in all clinical trials,injection-site reactions were seen to be the most frequent adversereactions and were reported by the majority of patients receiving GA. Incontrolled studies, the proportion of patients reporting thesereactions, at least once, was higher following treatment with GA (70%)than placebo injections (37%). The most commonly reported injection-sitereactions, which were more frequently reported in GA vs. placebo-treatedpatients, were erythema, pain, mass, puritus, edema, inflammation andhypersensitivity.

However, several obstacles and limitations with potential approaches foraddressing the drawbacks exist to current GA therapy. Subcutaneous drugdelivery is limited, firstly, by the acceptable injection volume.Typically no more than 1 to 2 ml of solution is permitted (Kansara V,Mitra A, Wu Y, Subcutaneous Delivery. Drug Deliv Technol, June 2009;9(6):38-42). Secondly, the potential exists for drug degradation at thesite of injection resulting in reduced bioavailability. Thirdly, basedon the physiochemical properties of the drug, potent compounds maybecome locally trapped in the interstitial space which can lead tofurther localized irritation, precipitation of the drug andconcentration-dependent adverse effects (Kansara V, Mitra A, Wu Y,Subcutaneous Delivery. Drug Deliv Technol, June 2009; 9(6):38-42).Finally, due to the complex pharmacokinetic behavior of a drug,variation in the frequency of administration is unpredictable andrequires empirical testing. For example, although controlled clinicaltrials have demonstrated the efficacy of IFNβ-1b in the treatment of MS,patient compliance, efficacy and tolerability are affected by the dosageregimen used. Merely increasing the dose of IFNβ-1b is insufficient toincrease efficacy, the frequency of administration must also beincreased (Luca Durelli, J Neurol (2003) 250 [Suppl 4]).

Accordingly, the subject application discloses an effective lowfrequency dosage regimen of GA administration to patients suffering froma relapsing form of multiple sclerosis, including patients who haveexperienced a first clinical episode and have MRI features consistentwith multiple sclerosis. Based on the performance of the dosage regimenin these studies, the administration of three s.c. injections over aperiod of seven days with at least one day between every injection isalso expected to work in the treatment of patients who have experienceda clinically isolated syndrome (CIS). This is based on the fact that the20 mg daily s.c. injection has been shown to work in PCT InternationalApplication No. PCT/US2008/013146 (see International Publication No. WO2009/070298 and also U.S. Patent Application Publication No. US2009-0149541 A1).

1. A method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient. 2.-21. (canceled)
 22. A method of increasing the tolerability of GA treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis which comprises reducing the frequency of subcutaneous injections of a pharmaceutical composition comprising a therapeutically effective dose of glatiramer acetate to three times over a period of seven days with at least one day between every injection. 23.-32. (canceled) 